Method of inhibiting dopamine beta-hydroxylase

ABSTRACT

A METHOD OF INHIBITING THE FORMATION OF DOPAMINE BHYDROXYLASE WHICH COMPRISES THE ADMINISTRATION TO A HOST OF A THERAPEUTICALLY-EFFECTIVE AMOUNT OF A PYRIMIDINE.

United States Patent 3,701,831 METHOD OF INHIBITING DOPAMINEfi-HYDROXYLASE Curt C. Porter, Glenside, Pa., assignor to Merck & Co.,Inc., Rahway, NJ. N0 Drawing. Filed Nov. 19, 1969, Ser. No. 878,209 Int.Cl.'A61k 27/00 US. Cl. 424-251 2 Claims ABSTRACT OF THE DISCLOSURE Amethod of inhibiting the formation of dopamine B- hydroxylase whichcomprises the administration to a host of a therapeutically-effectiveamount of a pyrimidine.

This invention relates to a method of inhibiting dopamine B-hydroxylasein patients (animal or human) utilizing novel pharmaceuticalcompositions containing thioureas and thioamides.

This invention further relates to a method of inhibiting alcoholmetabolism in patients (animal or human) utilizing novel pharmaceuticalcompositions containing thioureas and thioamides.

More particularly, this invention relates to the inhibition ofdopamine-fi-hydroxylase, an enzyme occurring in nerve tissue (centraland peripheral) and in the adrenal medulla, which catalyses theconversion of 3,4-dihydroxyphenethylamine (Dopamine) to norepinephrine.As a consequence of inhibiting this enzyme in vivo, the rate ofperipheral tissue norepinephrine synthesis is reduced, thereby resultingin decreased cardiac sympathetic stimulation. Centrally, norepinephrineconcentrations are reduced while dopamine concentrations are elevated,resulting in decreased activity in nonadrenergic neural pathways andincreased activity in dopaminergic neural pathways. Furthermore, thethioureas and thioamides of this invention are useful in thetreatment'of alcoholism as they act on the enzymes which normallyoxidize alcohol in the body thereby inhibiting the metabolic degradationof alcohol in the body.

'Still more particularly, this invention relates to pharmaceuticalcompositions having as an active ingredient compounds of the formula:

in which:

R may be hydrogen, loweralkyl, cycloloweralkyl, aryl,

substituted aryl, aralkyl, heterocyclic, substituted heterocyclic,amino, substituted amino of the formula R4 S R4 S R4 N -d-N and -R:f1N IR R5 in which R is loweralkyl; and

R R R and R each may be hydrogen, loweralkyl,

aryl or heterocyclic and wherein ylbutyl; the term heterocyclic includesthienyl, furyl pyrrolyl, imidazolyl, pyridyl, pyrazolyl, etc.; and theheterocyclic groups may be alkyl or halo substituted. When R and R arejoined to form a heterocyclic compound, heterocycles and substitutedheterocycles such as pyrazoles, imidazoles, pyrrolidines, pyrroles,piperidines, pyridines, pyridazines, pyrimidenes and benzimidazoles maybe formed.

It is to be understood that other substituents such as alkoxy, alkenyl,haloalkyl, etc. and heterocyclic groups such as indolyl, indenyl, etc.are considered within the scope of this application in that they arefunctionally equivalent to the above enumerated groups.

The compounds useful in the compositions of this invention may beprepared by well-known prior art methods. For example, the non-cyclicthioureas may be prepared by the methods disclosed on pp. 598-601 ofSemimicro Qualitative Analysis, Interscience Publishers, 1965; thethioamides may be prepared by the addition of hydrogen sulfide to thecorresponding nitrile as disclosed on p. 301 of Organic Chemistry,McGraw-Hill Book Company, 1959; the pyrazole-l-thiocarboxamidederivatives may be prepared by the procedure illustrated in 91 Chem.Ber. -57, 1958; and the pyrimidines may be prepared by the proceduresillustrated in United :States Letters Patent No. 2,539,480.

A preferred embodiment of this invention is a method of inhibitingdopamine fl-hydroxylase which comprises the administration of atherapeutically effective amount of the compounds of the above formula.In general the daily dose can be from 0.05 mg./kg. to 500 mg./kg. perday and preferably from 1 mg./kg. to 250 mg./kg. per day, bearing inmind, of course, that in selecting the appropriate dosage in anyspecific case, consideration must be given to the patients weight,general health, metabolism, age and other factors which influenceresponse to the drug.

Another embodiment of this invention is the provision of pharmaceuticalcompositions in dosage unit form which comprise from about 1 mg. to 1 g.of a compound of the above formula.

Still another preferred embodiment of this invention is a method ofinhibiting alcohol metabolism which comprises the administration indosage unit form of from 0.05 mg./kg. to about 500 mg./kg. per day andpreferably from 1 mg./kg. to 250 mg./ kg. per day of a compound of theabove formula.

Some of the more preferred compounds utilized in the methods andcompositions of this invention are thiobutyrolactam and4,4,6-trimethyl-3,4-dihydropyrimdine- 2-thiol.

The pharmaceutical compositions may be in a form suitable for oral use,for example, as tablets, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to provide apharmaceutically elegant and palatable preparation. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for manufacture of tablets.These excipients may be, for example, inert diluents, for examplecalcium carbonate, sodium carbonate, lactose, calcium phosphate orsodium phosphate, granulating and disintegrating agents, for examplemaize starch, or alginic acid; binding agents, for example starch,gelatine or acacia; and lubricating agents, for example magnesiumstearate, steric acid or talc. The

tablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer'period.

Formulations for oral use may also be presented as hard gelatinecapsules wherein the active ingredient is mixed with an inert soliddiluent, for example calcium carbonate, calcium phosphate or kaolin, oras soft gelatine capsules whereinthe active ingredient is mixed with anoil medium, for example arachis oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active thioamides or thioureas inadmixture with excepients suitable for the manufacture of aqueoussuspensions. Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate or condensationproducts of ethylene oxide with long chain aliphatic alcohols forexample heptadecaethyleneoxy-cetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol, for example polyoxyethylene sorbitol mono-oleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitonmono-oleate. The said aqueous sus 1 pensions may also contain one ormore preservatives, for

example ethyl, or n-propyl, p-hydroxy benzoate, one or more coloringagents, one or more flavoring agents and one or more sweetening agents,such as sucrose, saccharin, or sodium or calcium cyclamate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, fiavoring and coloringagents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents. Thepharmaceutical compositions may be in the form of a sterile injectablepreparation, for example as a sterile injectable aqueous suspension.This suspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol.

The pharmaceutical compositions may be tableted or otherwise formulatedso that for every 100 parts by weight of the composition there arepresent between 5 and 95 parts by weightof the active ingredient andpreferably between 25 and 85 parts by weight of the active ingredient.The dosage unit form will generally contain between about 100 mg. andabout 500 mg. of the active ingredient of the formula stated above.

From the foregoing formulation discussion it is apparent that thecompositions of this invention can be administered orally orparenterally. The term parenteral as 4 used herein includes subcutaneousinjection, intravenous, intramuscular, or intrasternal injection orinfusion techniques.

This invention is further demonstrated by the following examples inwhich all parts are by weight.

EXAMPLE. 1

A mixture of 250 parts of 4,4, 6-trimethyl-3,4-dihydropyrimidine-Z-thioland 25 parts of lactose is granulated with suitable water and to this isadded parts of maize starch. The mass is passed through a 16-meshscreen. The granules are dried at a temperature below 60 C. The drygranules are passed through a l6-mesh screen and mixed with 3.8 parts ofmagnesium stearate. They are then compressed into tablets suitable fororal administration according to the method of this invention.

EXAMPLE 2 A mixture of 50 parts of thiobutyrolactam, 3 parts of thecalcium salt of lignin sulfonic acid,- and 237 parts of water isball-milled until the size of substantially all the particles ofthiobutyrolactam is less than 10 microns. The suspension is diluted witha solution containing 3 parts of sodium carboxymethylcellulose and 0.9part of the. butyl ester of p;hydroxybenzoic acid in 300 parts of water.There is thus obtained an aqueous suspension suitable for oraladministration for therapeutic purposes.

EXAMPLE 3 A mixture of 250 parts of 5-methylthiobutyrolactam, 200 partsof maize starch and 30 parts of alginic acid is mixed with a suflicientquantity of a 10% aqueous paste of maize vstarch'and granulated. Thegranules are dried in a current of warm air and the dry granules arethen passed through a 16-mesh screen, mixed with 6 parts of magnesiumstearate and compressed into tablet form to obtain tablets suitable fororal administration.

EXAMPLE 4 (A) A mixture of 500 parts of4,4,5,5-tetramethylimidazoline-Z-thione, 60 parts of maize starch and 20parts of gum acacia is granulated with a suflicient quantity of water.The mass is passed through a 12-mesh screen and the granules are driedin a current of warm air. .The dry granules are passed through a 16-meshscreen, mixed with 5 parts of magnesium stearate and compressed intotablet form suitable for oral administration.

(B) Other therapeutically effective compounds within the scope of thisinvention include: thioacetanilide, thiobenzamide, Z-mercaptopyridine,thiopiperidone, dithiooxamide, N,N-dimethyl-dithiooxamide,l-methyl-Z-mercaptoimidazole, malonothionamide,3-methylpyrazole-l-thiocarboxamide and 2-ethylisothionicotinamide.

What is claimed is:

1. A method of inhibiting dopamine B-hydroxylase which comprisesadministering to a host requiring the inhibition of dopamineB-hydroxylase a therapeutically effective amount of4,4,6-trimethyl-3,4-dihydropyrimidine- 2-thiol.

2. A method as in claim 1 wherein the therapeutically effective amountis from about 1 to 250 mg./kg. per day.

References Cited Chem. Abst. Subject Index, vol. 56-65 (1962-1966), p.7800s.

SAM ROSEN, Primary Examiner

